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Development of an Adverse Outcome Pathway for Deposition of Energy Leading to Learning and Memory Impairment
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  • Ahmad Sleiman,
  • Kathleen Miller,
  • Danicia Flores,
  • Jaqueline Kuan,
  • Kaitlyn Altwasser,
  • Benjamin Smith,
  • Tatiana Kozbenko,
  • Robyn Hocking,
  • Scott Wood,
  • Janice Huff,
  • Christelle Adam-Guillermin,
  • Nobuyuki Hamada,
  • Carole Yauk,
  • Ruth Wilkins,
  • Vinita Chauhan
Ahmad Sleiman
Institut de radioprotection et de Sûreté Nucléaire
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Kathleen Miller
National Institute of Aerospace
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Danicia Flores
Health Canada
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Jaqueline Kuan
Health Canada
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Kaitlyn Altwasser
Health Canada
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Benjamin Smith
Health Canada
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Tatiana Kozbenko
Health Canada
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Robyn Hocking
Health Canada
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Scott Wood
NASA Johnson Space Center
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Janice Huff
NASA Langley Research Center
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Christelle Adam-Guillermin
Institut de radioprotection et de Sûreté Nucléaire
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Nobuyuki Hamada
Central Research Institute of Electric Power Industry
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Carole Yauk
University of Ottawa
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Ruth Wilkins
Health Canada
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Vinita Chauhan
Health Canada

Corresponding Author:vinita.chauhan@hc-sc.gc.ca

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Abstract

The understanding of radiation-induced non-cancer effects on the central nervous system (CNS) is essential for the medical setting (e.g., radiotherapy), and occupational exposures, such as nuclear workers or astronauts. Herein, the adverse outcome pathway (AOP) approach was used to consolidate relevant studies in the area of cognitive decline for identification of research gaps, countermeasure development, and for eventual use in risk assessments. AOPs are an analytical construct describing critical events to an adverse outcome (AO) in a simplified form beginning with a molecular initiating event (MIE). An AOP was constructed utilizing mechanistic information to build empirical support for the key event relationships (KERs) between the MIE of deposition of energy to the AO of learning and memory impairment through multiple key events (KEs). The evidence for the AOP was developed through a scoping review of the literature. In this AOP, the MIE is connected to the AO via six KEs of increased oxidative stress, increased deoxyribonucleic acid (DNA) strand breaks, altered signaling pathways, tissue resident cell activation, increased pro-inflammatory mediators and neural remodeling. Deposition of energy directly leads to oxidative stress, increased DNA strand breaks, an increase of pro-inflammatory mediators and tissue resident cell activation. These KEs, which are themselves interconnected, converge through increased DNA strand breaks, altered signaling pathways and pro-inflammatory routes and directly lead to neural remodeling. Broadly, it is envisioned that the outcome of these efforts could be applied to other cognitive disorders and support ongoing work by international authorities to review the system of radiological protection.
18 May 2023Submitted to Environmental and Molecular Mutagenesis
19 May 2023Submission Checks Completed
19 May 2023Assigned to Editor
19 May 2023Review(s) Completed, Editorial Evaluation Pending
06 Jun 2023Reviewer(s) Assigned
14 Aug 2024Editorial Decision: Accept